Die Erfindung betrifft ein Verfahren zur Herstellung vonchimeren monoclonalen Antikörpern. Insbesondere betrifftdiese Erfindung die Herstellung von chimeren monoclonalenAntikörpern, deren Nebenwirkungen, wie Anaphylaxie undSerumallergie, stark reduziert sein sollen, insbesondere wennsie einem Menschen verabreicht werden.The invention relates to a method for producing chimeric monoclonal antibodies. In particular, this invention relates to the production of chimeric monoclonal antibodies whose side effects, such as anaphylaxis and serum allergy, are said to be greatly reduced, especially when administered to a human.
Ein monoclonaler Antikörper mit Monospezifität erhielteinen großen Einfluß in der Immunologie, und seineNützlichkeit wurde bereits in solchen Wissenschaften, wieder Biologie, der Pharmakologie, der Chemie und anderennachgewiesen.A monoclonal antibody with monospecificity has had a great impact in immunology, and its usefulness has already been proven in such sciences as biology, pharmacology, chemistry and others.
Was ihr Herstellungsverfahren betrifft, so gelang dieDurchführung 1975 Köhler und Milstein durch Fusion vonMausmilzzellen, die mit Schaferythrocyten sensibilisiertworden waren, und Mausmelanomzellen (vergleiche Nature;256, 495-497 (1975)). Abgesehen davon gibt es ein anderesVerfahren, bei dem das Epstein-Barr-Virus verwendet wird(vergleiche offengelegte japanische Patentpublikation Nr.sho 58-201723).As for their production method, it was achieved by Köhler and Milstein in 1975 by fusing mouse spleen cells sensitized with sheep erythrocytes and mouse melanoma cells (see Nature; 256, 495-497 (1975)). Apart from that, there is another method using Epstein-Barr virus (see Japanese Patent Laid-Open Publication No. sho 58-201723).
Da sich jedoch die meisten monoclonalen Antikörper vonTieren, ausgenommen des Menschen, ableiten, nimmt man an, daßsie solche Nebenwirkungen wie Anaphylaxie oderSerumkrankheit bei Verabreichung an den Menschen verursachen, weilheterologe Proteine in einen menschlichen Körper injiziertwerden. Folglich wurden bis jetzt verschiedene Versucheunternommen, um vom Menschen abgeleitete monoclonaleAntikörper unter Verwendung von menschlichen Hybridomenherzustellen. Unter diesen sind die japanischen PatentpublikationNr. sho 57-126424, sho 57-502090, sho 58-90517, sho 58-128323 und sho 57-50209 beispielsweise.However, since most monoclonal antibodies are derived from animals other than humans, they are considered to cause such side effects as anaphylaxis or serum sickness when administered to humans because heterologous proteins are injected into a human body. Accordingly, various attempts have been made to date to produce human-derived monoclonal antibodies using human hybridomas. Among them, Japanese Patent Publication Nos. sho 57-126424, sho 57-502090, sho 58-90517, sho 58- 128323 and sho 57-50209 for example.
Diese Versuche besagen, daß die Herstellung von, von- einemMenschen abgeleiteten, monoclonalen Antikörpern mitSicherheit möglich ist, aber immer noch unzureichend angesichtsdessen Reproduzierbarkeit und anderer Gesichtspunkte ist(vergleiche Nature; 300, 316-317 (1982)). Zusätzlichbesteht ein Nachteil dahingehend, daß die Immunisierung desMenschen mit irgendeinem gewünschten Antigen unmöglich ist,obwohl die Immunisierung von Tieren, wie Mäusen, mitverschiedenen Antigenen möglich ist.These experiments indicate that the production of human-derived monoclonal antibodies is certainly possible, but is still insufficient in terms of its reproducibility and other aspects (see Nature; 300, 316-317 (1982)). In addition, there is a disadvantage in that immunization of humans with any desired antigen is impossible, although immunization of animals such as mice with various antigens is possible.
In dieser Hinsicht wurde ein Versuch unternommen, coliformeBakterien zur Erzeugung eines vom Menschen abgeleitetenmonoclonalen Antikörpers durch Insertion einer komplementärenDNA in das Plasmid pBR 322 zu veranlassen. Diese cDNA wurdedurch u-Ketten spezifische mRNA, erhalten aus Mensch-Maus-Hybridomen, die menschliche monoclonale Antikörpererzeugen, erhalten. Da es jedoch unmöglich ist, den Menschen mitverschiedenen Antigenen, soweit gewünscht, zu immunisieren,muß gesagt werden, daß hier noch ein Problem besteht.In this regard, an attempt was made to induce coliform bacteria to produce a human-derived monoclonal antibody by inserting a complementary DNA into the plasmid pBR 322. This cDNA was replaced by u-chain specific mRNA obtained from human-mouse hybridomas producing human monoclonal antibodies. However, since it is impossible to immunize humans with different antigens as desired, it must be said that a problem still exists here.
Die EP-A-0 125 023 beschreibt ein Verfahren zur Herstellungvon chimeren Antikörpern bzw. Immunglobulinen, die solchen,die normalerweise in vertebraten Systemen gefunden werden,analog sind. Proc. Natl. Acad. Sci. USA, Bd. 81, Seiten3273-3277, Juni 1984, beschreibt die Konstruktion vonPlasmiden aus H- und/oder L-Ketten von CEA-Antikörpern, diedirekt in E. coli erzeugt werden.EP-A-0 125 023 describes a process for producing chimeric antibodies or immunoglobulins analogous to those normally found in vertebrate systems. Proc. Natl. Acad. Sci. USA, vol. 81, pages 3273-3277, June 1984, describes the construction of plasmids from H and/or L chains of CEA antibodies produced directly in E. coli.
Unter diesen Umständen führten die genannten Erfinderverschiedene Studien durch, um die vorstehenden Nachteile zubeseitigen und führten schließlich diese Erfindung aus. Dasheißt, die Erfindung betrifft ein Verfahren zur Herstellungvon chimeren monoclonalen Antikörpern, bestehend aus einer,von einer Maus abgeleiteten, variablen Region und einer vomMenschen abgeleiteten konstanten Region, dadurchgekennzeichnet, daß man (a) in einen Expressionsvektor dieaktiven VH- und VL-Gene isoliert, von Hybridomen alsAntikörper-erzeugenden Zellen der Maus, und die aktiven Gene CHund CL, isoliert aus menschlicher DNA, insertiert und dann(b) einen Expressionsvektor aus (a) in Lymphomazellen alsgezüchtete tierische Zellen einbringt.Under these circumstances, the present inventors conducted various studies to eliminate the above drawbacks and finally completed this invention. That is, the invention relates to a method for producing chimeric monoclonal antibodies consisting of a, from a mouse-derived variable region and a human-derived constant region, characterized in that (a) the active VH and VL genes isolated from hybridomas as antibody-producing cells of the mouse and the active CH and CL genes isolated from human DNA are inserted into an expression vector and then (b) an expression vector from (a) is introduced into lymphoma cells as cultured animal cells.
Es ist eine Aufgabe dieser Erfindung, ein Verfahren zurHerstellung von chimeren monoclonalen Antikörpernbereitzustellen, deren Nebenwirkungen, wie anaphylaktischer Schockund Serumkrankheit, stark reduziert sind, indem einevariable Region, abgeleitet von einer Maus und eine konstanteRegion, abgeleitet von einem Menschen kombiniert werden,weil die meisten herkömmlichen monoclonalen Antikörper sichausschließlich von Tieren, ausgenommen des Menschenableiten und so vermutlich eine Ursache für solcheNebenwirkungen, wie anaphylaktischer Schock und Serumkrankheit beiVerabreichung an einen menschlichen Körper aufgrund derTatsache, daß sie heterologe Proteine sind, sind.It is an object of this invention to provide a method for producing chimeric monoclonal antibodies whose side effects such as anaphylactic shock and serum sickness are greatly reduced by combining a variable region derived from a mouse and a constant region derived from a human, because most of the conventional monoclonal antibodies are derived exclusively from animals other than humans and thus are presumed to be a cause of such side effects such as anaphylactic shock and serum sickness when administered to a human body due to the fact that they are heterologous proteins.
Dieses Herstellungsverfahren kann leicht mit reduziertenKosten und Sicherheit industrialisiert werden.This manufacturing process can be easily industrialized with reducedcosts and safety.
Die vorstehenden und anderen Aufgaben und Besonderheitendieser Erfindung gehen nachher deutlicher aus einerBetrachtung der folgenden Beschreibung zusammen mit denbeigefügten Zeichnungen, worin ein Beispiel als Beispielangegeben ist, hervor.The foregoing and other objects and features of this invention will hereinafter become more apparent from a consideration of the following description taken in conjunction with the accompanying drawings, in which an example is given by way of example.
Fig. 1 ist eine Röntgenphotographie, die das Ergebnis derSouthern Hybridisierung zeigt, die durchgeführt wurde, umaktives Maus-V-Gen und menschliches C-Gen zu isolieren undder mRNA Northern-Blotting-Analyse davon; Fig. 1Berläutert schematisch die verschiedenen Clone, die ausHybridomen und einer menschlichen Gen-Bank isoliert wurden, worin(a) den Clon VJχ 14, (b) den Clon VJH 243, (c) den Clon HCχ2, und (d) den Clon HG 163 erläutert.Fig. 1 is an X-ray photograph showing the result of Southern hybridization performed to active mouse V gene and human C gene and mRNA Northern blotting analysis thereof; Figure 1B illustrates schematically the various clones isolated from hybridomas and a human gene library, in which (a) clone VJχ 14, (b) clone VJH 243, (c) clone HCχ 2, and (d) clone HG 163.
Fig. 2 zeigt Plasmidstrukturen, die zur Verwendung für dieDNA-Transformation gebildet wurden, worin (a) die Strukturdes Plasmids pSV2-HCKVD10 und (b) die Struktur des PlasmidspSV2-HGIVD10 zeigt;Figure 2 shows plasmid structures constructed for use in DNA transformation, in which (a) shows the structure of plasmid pSV2-HCKVD10 and (b) shows the structure of plasmid pSV2-HGIVD10;
Fig. 3 zeigt Diagramme einer FACS-Analyse, undFig. 3 shows diagrams of a FACS analysis, and
Fig. 4A ist eine Röntgenphotographie, die das Ergebnis derDNA Southern Hybridisierung mit HMH-Zellen zeigt; Fig. 4Bist eine Röntgenphotographie, die das Ergebnis der mRNANorthern-Blotting-Analyse zeigt.Fig. 4A is an X-ray photograph showing the result ofDNA Southern hybridization with HMH cells; Fig. 4Bis an X-ray photograph showing the result of mRNANorthern blotting analysis.
Der hier verwendete Ausdruck "aktive VH- und VL-Gene",bedeutet funktionelle Gene, die die Struktur V-D-Jhinsichtlich VH und die Struktur V-J hinsichtlich VL besitzen, mitder Maßgabe, daß VH und VL durch die DNA-Anordnung inAntikörper-erzeugenden Zellen gebildet werden.The term "active VH and VL genes" as used herein means functional genes having the structure V-D-J with respect to VH and the structure V-J with respect to VL, provided that VH and VL are formed by the DNA arrangement in antibody-producing cells.
Hybridome, clonierte B-Zellen und B-Zellen, die mit demEpstein-Barr-Virus transformiert sind, werden bevorzugt alsdie Antikörper-erzeugenden Zellen verwendet; und dieVektoren pSV2-gpt, pSV2-neo und SV40 werden bevorzugt als die"Expressionsvektoren" verwendet.Hybridomas, cloned B cells and B cells transformed with Epstein-Barr virus are preferably used as the antibody-producing cells; and the vectors pSV2-gpt, pSV2-neo and SV40 are preferably used as the "expression vectors".
Jedoch können beliebige Zellen ausgewählt ausLymphomazellen, Nierenzellen, L-Zellen, COS-Zellen und HeLa-Zellenabgeleitet von einer Maus als "gezüchtete tierische Zellen"verwendet werden.However, any cells selected fromlymphoma cells, kidney cells, L cells, COS cells and HeLa cellsderived from a mouse can be used as "cultured animal cells".
Mittlerweile sind erfindungsgemäß Mäuse so leicht zuimmunisieren, daß jeder beliebige chimere monoclonaleAntikörper erhalten werden kann. Zur gleichen Zeit wirdnatürlicherweise erwartet, daß die Antigenizität der heterologenImmunglobulinproteine stark bei der Verwendung dererfindungsgemäßen chimeren monoclonalen Antikörper, verglichenmit anderen, die sich nur von Tieren ableiten, verringertwird.Meanwhile, mice are so easy to immunize according to the invention that any chimeric monoclonal antibody can be obtained. At the same time, it is naturally expected that the antigenicity of the heterologous immunoglobulin proteins will be greatly reduced using the chimeric monoclonal antibodies of the invention as compared with others derived only from animals.
Die vorliegende Erfindung wird anhand des folgendenBeispiels näher erläutert.The present invention is explained in more detail using the following example.
Das Hybridom D10, früher als M2590 bezeichnet, ist diefusionierte Zelle zwischen der aufnehmenden Tumorzelle P3U1und der, von der C57BL/6 Maus abgeleiteten Milzzelle, diemit einer B-16 Melanomzelle, die spontan in einer C57BL/6Maus erzeugt wurde, immunisiert wurde. D10 scheidet denAntikörper, der mit den Melanomzellen selektiv reagiert, aus.Die Art dieses Antikörpers ist IgM für die schwere Ketteund Kappa für die leichte Kette.Hybridoma D10, formerly called M2590, is the fused cell between the host tumor cell P3U1 and the C57BL/6 mouse-derived spleen cell immunized with a B-16 melanoma cell spontaneously generated in a C57BL/6 mouse. D10 secretes the antibody that reacts selectively with the melanoma cells. The type of this antibody is IgM for the heavy chain and kappa for the light chain.
Zuerst wird DNA aus D10, P3U1 bzw. C57BL/6 Mausnierenisoliert (vergleiche Cell; 24, 353-356 (1981)). Als nächsteswerden 10 ug DNA mit dem Restriktionsenzym Hind III undEcoRI abgebaut. D10, P3U1 und die von der C57BL/6 Mausabgeleitete DNA, welche mit Hind III abgebaut wurden, werdenin einem 0,9%igen Agarosegel entwickelt und aufNitrocellulosemembran überführt (siehe Schleicher and Schvell; J.Mol. Biol., 98, 503-515 (1975)). Andererseits wird dieHybridisierung mit einer Jχ-Sonde (10&sup7; cpm/0,1 ug DNA), diedem 2,7 Kb Hind III-Hind III-Fragment, das die Jχ-Regionenthält, welches von Mr. Susumu Tonegawa (vergleicheNature; 280, 288-294 (1979)) zur Verfügung gestellt wurde,entspricht, durchgeführt. Das Ergebnis ist in Fig. 1A(a)gezeigt.First, DNA is isolated from D10, P3U1 and C57BL/6 mouse kidneys, respectively (see Cell; 24, 353-356 (1981)). Next, 10 µg of DNA is digested with the restriction enzyme Hind III and EcoRI. D10, P3U1 and the DNA derived from the C57BL/6 mouse, which was digested with Hind III, are developed in a 0.9% agarose gel and transferred to nitrocellulose membrane (see Schleicher and Schvell; J. Mol. Biol., 98, 503-515 (1975)). On the other hand, hybridization is carried out with a Jχ probe (10⁷ cpm/0.1 µg DNA) which the 2.7 Kb Hind III-Hind III fragment containing the Jχ region, which was provided by Mr. Susumu Tonegawa (see Nature; 280, 288-294 (1979)). The result is shown in Fig. 1A(a).
Wie aus Fig. 1A(a) hervorgeht, existieren drei neuangeordnete Banden bei 6,5, 6,3 und 6,1 Kb in der D10 DNA. Diezwei Banden bei 6,3 und 6,1 Kb sind die gleichen wie die,die in der P3U1 DNA gefunden wird. Die Bande bei 6,5 Kb istein aktives Gen, das die Vχ-Jχ-Struktur enthält. Dieses Genist für dessen Antigenspezifität verantwortlich. Die Größeder DNA wird unter Verwendung des λ-Phagen als Marker fürHind III abgeschätzt. Die DNA-Fragmente, die dieser Größeentsprechen, werden mittels Agarosegel-Elektrophoreseisoliert, in den λ-Phagen-Hind III Vektor λ 788 insertiert,der von Mr. K. Murray der Edingburgh University zurVerfügung gestellt wurde (vergleiche Mole. Gen. Genet.; 150, 53-61 (1977)) und dann in λ-Phagen verpackt. Die coliformenBakterien BHB 2688 und BHB 2690 werden alsVerpackungsgemisch verwendet (vergleiche Hohn. B. Meth. Enzymol.; 68,299-309 (1979)). Als nächstes wird diePlaque-Hybridisierung gemäß dem Benton-Davis-Verfahren (Science, 196,180-182 (1977)) unter Verwendung einer Jχ-Sonde zum Absuchendurchgeführt. Der Clon VJχ-14 wird isoliert. DieRestriktionskarte des Clons ist in Tabelle 1B(a) angegeben.As shown in Fig. 1A(a), three rearranged bands at 6.5, 6.3 and 6.1 Kb exist in the D10 DNA. The two bands at 6.3 and 6.1 Kb are the same as those found in the P3U1 DNA. The band at 6.5 Kb is an active gene containing the Vχ-Jχ structure. This gene is responsible for its antigen specificity. The size of the DNA is estimated using the λ phage as a marker for Hind III. The DNA fragments corresponding to this size are isolated by agarose gel electrophoresis, inserted into the λ phage-Hind III vector λ 788 provided by Mr. K. Murray of Edinburgh University (see Mole. Gen. Genet.; 150, 53-61 (1977)) and then packaged into λ phages. Coliform bacteria BHB 2688 and BHB 2690 are used as packaging mixture (see Hohn. B. Meth. Enzymol.; 68, 299-309 (1979)). Next, plaque hybridization is carried out according to the Benton-Davis method (Science, 196, 180-182 (1977)) using a Jχ probe for screening. Clone VJχ-14 is isolated. The restriction map of the clone is given in Table 1B(a).
Das mit Hind III insertierte VJχ-Fragment wird isoliert, umdie Northern Hybridisierung durchzuführen. Die Gesamt-RNAwird aus D10 nach dem Guanidinium-Thiocyanat-Verfahrenisoliert (Biochemistry; 18, 5294-5299 (1979)); danach wirdPoly-A-haltige mRNA aus den Fraktionen, die durch dieOligo-dT-Cellulosesäule gelaufen sind, erhalten. Die Fig.1A(b) zeigt die Northern Hybridisierung von mRNA plus demHind III-insertierten Clon VJχ-14-Fragment oder der mRNAplus Cχ-Sonde, die dem 3Kb Hind III-BamHI-Fragment,enthaltend die Cχ-Region entspricht, welches von Mr. SusumuTonegawa zur Verfügung gestellt wurde (vergleiche Nature; 280,288-294 (1979)). Eine Bande wird bei 1,2 Kb mit den zweiSonden Jχ und Cχ beobachtet. Der Clon VJχ14 enthält diefunktionelle Vχ-Jχ-Struktur. Wie die NorthernHybridisierung durchzuführen ist, ist in ImmunologicalExperimental Procedures XII (1983) beschrieben.The Hind III-inserted VJχ fragment is isolated to perform Northern hybridization. Total RNA is isolated from D10 by the guanidinium thiocyanate method (Biochemistry; 18, 5294-5299 (1979)); then poly-A-containing mRNA is obtained from the fractions passed through the oligo-dT-cellulose column. Fig. 1A(b) shows Northern hybridization of mRNA plus the Hind III-inserted clone VJχ-14 fragment or mRNA plus Cχ probe corresponding to the 3 Kb Hind III-BamHI fragment containing the Cχ region, which was provided by Mr. Susumu Tonegawa (see Nature; 280, 288-294 (1979)). A band is observed at 1.2 Kb with the two probes Jχ and Cχ. Clone VJχ14 contains the functional Vχ-Jχ structure. How to perform Northern hybridization is described in Immunological Experimental Procedures XII (1983).
Fig. 1A(c) zeigt die Southern Hybridisierung der JH-Sonde,die dem Xbal-EcoRI-Fragment bei 0,9 Kb entspricht (Cell.;24, 353-365 (1981)) und die mit EcoRI abgebaute DNA.Fig. 1A(c) shows the Southern hybridization of the JH probe corresponding to the XbaI-EcoRI fragment at 0.9 Kb (Cell.; 24, 353-365 (1981)) and the EcoRI digested DNA.
Aus dem vorstehend erwähnten Grund wird die DNA bei 5,5 Kb,die sich nur in D10, das ein funktionelles Gen in dervariablen Region der H-Kette enthält, findet, in den λ-PhagenEcoRI-Vektor λgt WES-λB, (vergleiche P. Leader, Science;196, 175-177 (1977)) cloniert, und der Clon VJH243 wirderhalten. Der Clon VJH243 und die Cu-Sonde, die dem 10 KbEcoRI-Fragment von MEP 203 entspricht (Proc. Natl. Acad.Sci. USA: 77, 2138-2142 (1980)) werden verwendet, um dieNorthern-Blotting-Analyse mit mRNA von D10 durchzuführen.Als Ergebnis wird eine Bande bei 2,4 Kb gefunden (sieheFigur 1A(d)). Das V-Gen, das in den Clonen VJλ 14 und VJH243enthalten ist, steht im Bezug zu ihrer antigenenSpezifität.For the reason mentioned above, the DNA at 5.5 Kb,found only in D10, which contains a functional gene in the H chain variable region, is cloned into the λ phage EcoRI vector λgt WES-λB, (see P. Leader, Science; 196, 175-177 (1977)) and the clone VJH243 isobtained. The clone VJH243 and the Cu probe corresponding to the 10 Kb EcoRI fragment of MEP 203 (Proc. Natl. Acad. Sci. USA: 77, 2138-2142 (1980)) are used to perform theNorthern blotting analysis with mRNA of D10.As a result, a band is found at 2.4 Kb (seeFigure 1A(d)). The V gene contained in clones VJλ14 and VJH243is related to their antigenicspecificity.
Das C-Gen der IgG&sub1;-Klasse, die die Hauptimmunglobulinklasseim menschlichen Blutserum ist, wird isoliert. Insofern alsdie Nucleotidsequenz in Genen von menschlichemImmunglobulin eine große Ähnlichkeit zu der von Maus-Immunglobulinbesitzt, sollen die Cχ- und Cγ1-Gene, die in denmenschlichen Genomen vorhanden sind, unter Verwendung derentsprechendenMausgene als Sonde isoliert werden. Das heißt, HindIII-BamHI-Fragmente (3 Kb) aus dem Clon Ig 146 (Proc. Natl.Acad. Sci. USA; 78, 474-478 (1981)) werden als Sonde zurIsolierung von Fragmenten verwendet, die das Cχ-Genzusammen mit einer Enhancer-Region aus der Hae III-Alu-I-Genbankin dem λ-Charon 4A enthalten (T. Maniatis, Cell.; 15,1157-1174 (1978)). Die Cγ1-Gene werden durch Abbau der DNA ausmenschlichen fötalen Leberzellen mit Hind III,Fraktionieren der so erhaltenen DNA-Fragmente durchAgarosegel-Elektrophorese nach ihrer Größe, Insertieren eines Fragmentsbei 5,9 Kb in λ788 und abschließende Clonierung mit dervorstehenden Sonde erhalten. Die isolierten Clone sindHCχ2, wie in Fig. 1B(c) gezeigt und HG 163, wie in Fig.1B(d) gezeigt.The C gene of the IgG₁ class, which is the major immunoglobulin class in human blood serum, is isolated. Insofar as the nucleotide sequence in human immunoglobulin genes is very similar to that of mouse immunoglobulin, the Cχ and Cγ1 genes present in the human genomes are to be isolated using the corresponding Mouse genes are isolated as a probe. That is, Hind III-BamHI fragments (3 Kb) from the clone Ig 146 (Proc. Natl. Acad. Sci. USA; 78, 474-478 (1981)) are used as a probe to isolate fragments containing the Cχ gene together with an enhancer region from the Hae III-Alu I library in the λ-charon 4A (T. Maniatis, Cell.; 15, 1157-1174 (1978)). The Cγ1 genes are obtained by digesting DNA from human fetal liver cells with Hind III, fractionating the resulting DNA fragments by size by agarose gel electrophoresis, inserting a fragment at 5.9 Kb into λ788 and finally cloning with the above probe. The isolated clones are HCχ2 as shown in Fig. 1B(c) and HG 163 as shown in Fig. 1B(d).
Herstellung des Plasmids pSV2-HCχV&sub1;&sub0;, enthaltend das Maus-Vχ-Gen und das menschliche Cχ-Gen.Construction of plasmid pSV2-HCχV₁₀ containing the mouse Vχgene and the human Cχ gene.
Das P Pvu II Fragment bei 1,9 Kb, das Enhancerelemente unddas menschliche Cχ-Gen enthält, wird aus dem Clon HCχ2, derin Fig. 1B(c) gezeigt ist, isoliert.The P Pvu II fragment at 1.9 Kb containing enhancer elements andthe human Cχ gene is isolated from clone HCχ2 shownin Fig. 1B(c).
Nachdem ein 50/50 Gemisch des Hind III- und BamHI-Linkers(hergestellt von Takara Shuzo Co., Ltd.) damit ligiertwurde, wird das so aufgebaute Produkt mit Hind IIIabgebaut. Das so erhaltene Fragment wird mit einem HindIII-insertierten Fragment bei 6,5 Kb, das aus VJχ14 isoliertwurde, ligiert, und dann wird das so erhaltene Produkt mitBamHI in Fragmente, die fraktioniert werden, abgebaut. EinFragment bei 5,9 Kb wird mittels Agarosegel-Elektrophoreseisoliert. Das isolierte Fragment wird in pSV2gpt an derBamHI-Stelle insertiert. Die Richtung des insertierten Genswird durch die Restriktionskarte (vergleiche pSV2-HCχVD10in Fig. 2(a)) bestimmt.After a 50/50 mixture of the Hind III and BamHI linker (manufactured by Takara Shuzo Co., Ltd.) is ligated thereto, the thus-constructed product is digested with Hind III. The thus-obtained fragment is ligated with a Hind III-inserted fragment at 6.5 Kb isolated from VJχ14, and then the thus-obtained product is digested with BamHI into fragments, which are fractionated. A fragment at 5.9 Kb is isolated by agarose gel electrophoresis. The isolated fragment is inserted into pSV2gpt at the BamHI site. The direction of the inserted gene is determined by the restriction map (compare pSV2-HCχVD10 in Fig. 2(a)).
Herstellung des Plasmids pSV2-HG1VD10, enthaltend das Maus-VH-Gen und das menschliche Cγ1GenPreparation of plasmid pSV2-HG1VD10 containing the mouse VH gene and the human Cγ1 gene
Das Fragment mit der 8,2 Kb Hind III-Insertion wird aus demClon HG 163 isoliert. Seine beiden Enden werden in glatteEnden mit dem Klenow-Enzym umgewandelt und mit einem EcoRI-Linker (hergestellt von Takara Shuzo Co., Ltd.) abgebaut.Danach wird das Fragment mit EcoRI und BamHI abgebaut undin das EcoRI- und BamHI-geschnittene Plasmid pSV2-gptinsertiert. Auf diese Art wird der Clon pSV2-HG14, enthaltenddas menschliche Cγ1-Gen, erhalten. Das 5,5 KbEcoRI-Fragment wird aus dem Clon VJH243 isoliert und in die EcoRI-Schnittstelle pSV2-HG14 insertiert. Die Orientierung desinsertierten Gens wird mittels der Restriktionskartebestimmt. (vergleiche pSV2-HGIVD10 in Fig. 2(b)).The fragment containing the 8.2 Kb Hind III insertion is isolated from the clone HG 163. Its two ends are converted into blunt ends with Klenow enzyme and digested with an EcoRI linker (manufactured by Takara Shuzo Co., Ltd.).Then the fragment is digested with EcoRI and BamHI and inserted into the EcoRI and BamHI-cleaved plasmid pSV2-gpt.In this way, the clone pSV2-HG14 containing the human Cγ1 gene is obtained. The 5.5 Kb EcoRI fragment is isolated from the clone VJH243 and inserted into the EcoRI site pSV2-HG14. The orientation of the inserted gene is determined using the restriction map (compare pSV2-HGIVD10 in Fig. 2(b)).
Transformation von einem Plasmacytom mittels der PlasmidepSV2-CHχVD10 und pSV2-HC&sub1;VD10Transformation of a plasmacytoma using the plasmidspSV2-CHχVD10 and pSV2-HC&sub1;VD10
Die beiden DNAs pSV2-HCχVD10 und pSV2-HGIVD10 werden in dasMaus-Plasmacytom P3U1 mittels desCalciumphosphat-Copräzipitationsverfahrens (Proc. Natl. Acad. Sci. USA: 76,1373-1376 (1979)) eingeführt. Das Verfahren umfaßt die folgendenSchritte.The two DNAs pSV2-HCχVD10 and pSV2-HGIVD10 are introduced into the mouse plasmacytoma P3U1 by the calcium phosphate coprecipitation method (Proc. Natl. Acad. Sci. USA: 76, 1373-1376 (1979)). The method comprises the following steps.
(1) Die Lösung A wird zu der gleichen Menge der Lösung2·HeBS tropfenweise zugegeben.(1) Solution A is added dropwise to an equal amount of solution2·HeBS.
(2) Das Gemisch wird 30 Minuten lang bei Raumtemperatureninkubiert.(2) The mixture is incubated for 30 minutes at room temperature.
(3) Das Plasmacytom P3U1 wird mit Trypsin, so weit es inseine Stücke dissoziiert, behandelt. Danach wird dasKulturmedium RPMI 1640, das 10% fötales Kälberserumenthält, dazugegeben, um die Trypsinbehandlung zu beenden.(3) Plasmacytoma P3U1 is treated with trypsin until it dissociates into its pieces. Then, culture medium RPMI 1640 containing 10% fetal calf serum is added to complete the trypsin treatment.
(4) Das Kulturmedium wird bei 1500 UpM 5 Minuten langzentrifugiert, um die Zellen zu gewinnen.(4) The culture medium is centrifuged at 1500 rpm for 5 minutes to collect the cells.
(5) Die Zellen (2·10&sup7;) werden dem Kulturmedium ohne fötalesKälberserum tropfenweise zugesetzt.(5) The cells (2·10⁷) are added dropwise to the culture medium without fetal calf serum.
(6) Das Gemisch wird bei 1500 UpM 5 Minuten langzentrifugiert.(6) The mixture is centrifuged at 1500 rpm for 5 minutes.
(7) Die Zellen werden in der in dem ersten Schritthergestellten Lösung suspendiert.(7) The cells are suspended in the solution prepared in the first step.
(8) Das so erhaltene Gemisch wird bei 37ºC 30 Minuten langinkubiert.(8) The resulting mixture is incubated at 37ºC for 30 minutes.
(9) 5 ml davon werden in ein anderes Reagenzglas überführt.(9) 5 ml of it are transferred to another test tube.
(10) Das Kulturmedium RPMI 1640, das 10% fötalesKälberserum (45 ml) enthält, wird in das Reagenzglas gegeben.(10) The culture medium RPMI 1640 containing 10% fetal calf serum (45 ml) is added to the test tube.
(11) Die Zellsuspension (0,1 ml) wird in die 96 Cavitäteneiner Microtiterplatte, in der die Zellen zu 2·10&sup4;, bezogenauf die Anzahl, aufgeteilt werden können, gegeben.(11) The cell suspension (0.1 ml) is added to the 96 wells of a microtiter plate in which the cells can be divided into 2·10⁴ by number.
(12) Die Zellen werden 72 Stunden mit dem Kulturmedium RPMI1640, das 10% fötales Kälberserum enthält, gezüchtet.(12) Cells are cultured for 72 hours using RPMI 1640 culture medium containing 10% fetal calf serum.
(13) Das Kulturmedium wird durch das Kulturmedium RPMI1640, das 5 ug/ml Mycophenolsäure und 250 ug/ml Xanthinenthält, zusammen mit 10% fötalem Kälberserum ersetzt, umdie transformierten Zellen auszuwählen.(13) The culture medium is replaced with RPMI 1640 containing 5 μg/ml mycophenolic acid and 250 μg/ml xanthine together with 10% fetal calf serum to select the transformed cells.
Die Lösung A und die Lösung 2·HeBS haben die folgendeZusammensetzung: Lösung A (enthaltend 200 ul des Plasmids) (sterilisiert in einem Autoklaven) Redestilliertes H&sub2;OSolution A and solution 2·HeBS have the following composition: Solution A (containing 200 μl of plasmid) (sterilized in an autoclave) Redistilled H₂O
Lösung 2·HeBS pH 7,05Solution 2·HeBS pH 7.05
HEPES 10 g/lHEPES 10 g/l
NaCl 16 g/lNaCl 16 g/l
KCl 0,74 g/lKCl 0.74 g/l
Na&sub2;HPO&sub4;H&sub2;O 0,25 g/lNa₂HPO₄H₂O 0.25 g/l
Dextrose 2 g/lDextrose 2 g/l
Auswahl einer transformierten Zelle, die einen chimerenmonoclonalen Antikörper erzeugt.Selection of a transformed cell that produces a chimeric monoclonal antibody.
Um eine transformierte Zelle, die einen chimerenmonoclonalen Antikörper erzeugt, auszuwählen, werden dasEnzym-gekoppelte Antikörperverfahren und die Analyse mittels einesZellsortierers FACS (ein Produkt von Beckton-Dickinson Co.,Ltd.) verwendet. 18 Clone der transformierten Zellen wurdenunter Verwendung eines selektiven Kulturmediums, dasMycophenolsäure enthält, ausgewählt. Das Plasmacytom P3U1 unddie 18 Clone der transformierten Zellen werden am Wachsenbis zur vollen Größe in einer Platte, die das selektiveKulturmedium enthält, gehalten. Der Überstand dieserKulturmedien wird dem Enzym-gekoppelten Antikörperverfahren(Meth. Enzymol.; 70, 419-439 (1980)) unterworfen, um ihreFähigkeit zur Antikörpererzeugung zu überprüfen. DasErgebnis ist in Tabelle 1 dargestellt. Tabelle 1 Antikörper Zelle Kaninchen Anti-Mensch IgGFc-Antikörper CK-AntikörperTo select a transformed cell producing a chimeric monoclonal antibody, the enzyme-linked antibody method and analysis by a cell sorter FACS (a product of Beckton-Dickinson Co., Ltd.) are used. 18 clones of the transformed cells were selected using a selective culture medium containing mycophenolic acid. The plasmacytoma P3U1 and the 18 clones of the transformed cells are kept growing to full size in a plate containing the selective culture medium. The supernatant of these culture media is subjected to the enzyme-linked antibody method (Meth. Enzymol.; 70, 419-439 (1980)) to check its ability to produce antibodies. The result is shown in Table 1. Table 1 Antibody Cell Rabbit Anti-Human IgGFc Antibody CK Antibody
Es ist klar, daß 1·10&sup7; HMH-S7 Zellen etwa 100 ng/ml anchimerem monoclonalem Maus-Mensch-Antikörper in 10 ml desÜberstandes ihres Kulturmediums ausscheiden.It is clear that 1·10⁷ HMH-S7 cells secrete approximately 100 ng/ml of chimeric mouse-human monoclonal antibody in 10 ml of the supernatant of their culture medium.
Zellsorteranalyse der HMH-Zellen und P3U1 unter Verwendungvon Anti-Mensch-IgGCell sorter analysis of HMH cells and P3U1 usinganti-human IgG
HMH-Zellen und das Plastocytom P3U1 werden zweimal in Hanksausgeglichener Salzlösung (Gibco) gewaschen. Die Zellen(10&sup7;) werden in eine Lösung aus 750 ul Anfärbepufferlösungund 250 ul Kaninchen Anti-Mensch-Immunglobulin-Antikörperoder 1 ug/ml normalem Kaninchen-IgG gegeben. Die Lösungwird bei Raumtemperaturen eine Stunde lang inkubiert.Danach werden die Zellen dreimal in Hanks ausgeglichenerSalzlösung gewaschen. Die nachstehenden Verfahren sind diegleichen, die in dem Avidin-Biotin-Kit, der von VectorLaboratory Co., Ltd. auf den Markt gebracht wird, beschriebensind.HMH cells and P3U1 plastocytoma are washed twice in Hanks balanced salt solution (Gibco). The cells (107) are placed in a solution containing 750 μl of staining buffer solution and 250 μl of rabbit anti-human immunoglobulin antibody or 1 μg/ml of normal rabbit IgG. The solution is incubated at room temperature for one hour. After that, the cells are washed three times in Hanks balanced salt solution. The procedures below are the same as those described in the Avidin-Biotin kit marketed by Vector Laboratory Co., Ltd.
In der Kürze, die Zellen werden in 250 ul eines 1/200menschlichen IgG-behandelten Biotin-konjugiertenAnti-Kaninchen-IgG (1,5 mg/ml) gegeben und bei Raumtemperatur 1Stunde lang inkubiert. Anschließend wird dreimal mit Hank'sLösung gewaschen, in 250 ul einer 1/20 Avidin FITC-Lösung (5mg/ml) überführt, und dann bei Raumtemperatur 30 Minutenlang inkubiert.Briefly, cells are placed in 250 μl of a 1/200 human IgG-treated biotin-conjugated anti-rabbit IgG (1.5 mg/ml) and incubated at room temperature for 1 hour. They are then washed three times with Hank's solution, resuspended in 250 μl of a 1/20 avidin FITC solution (5 mg/ml) and then incubated at room temperature for 30 minutes.
Wieder wird dreimal mit Hank's Lösung gewaschen.Schließlich werden 10&sup6; Zellen in 1 ml eines Kulturmediums gegebenund der Analyse mittels eines Fluoreszenz-aktiviertenZellsorters (FACS IV), ausgestattet mit einem logarithmischenVerstärker, der von Beckton-Dickinson Co., Ltd. hergestelltwird, unterworfen. Das Ergebnis ist in Fig. 3 gezeigt.Again, wash three times with Hank's solution.Finally, 106 cells are placed in 1 ml of a culture mediumand subjected to analysis by a fluorescence-activated cell sorter (FACS IV) equipped with a logarithmic amplifier manufactured by Beckton-Dickinson Co., Ltd. The result is shown in Fig. 3.
In der FACS-Analyse werden HMH-Zellen als Zielzellen undKaninchen-IgG als Kontrolle verwendet. Das heißt, in Fig.3, (a) sind die HMH-Zellen gezeigt, die mit Kaninchen Anti-Mensch-Ig-Antikörper reagiert haben, (b) die mit KaninchenAnti-Mensch-χ-Antikörper reagiert haben und (c) die mitKaninchen Anti-Mensch-IgGFc-Antikörper reagiert haben. Aufähnliche Weise zeigt (d) die FITC-Profile derzusammengesetzten HMH-Zellen (R) und von P3U1 (L), das mit einemKaninchen Anti-Mensch-Ig-Antikörper, (e) mit einem KaninchenAnti-Mensch-χ-Kettenantikörper und (f) mit Kaninchen Anti-Mensch IgGFc-Antikörper behandelt wurden.In the FACS analysis, HMH cells are used as target cells and rabbit IgG as control. That is, in Fig. 3, (a) shows the HMH cells reacted with rabbit anti-human Ig antibody, (b) reacted with rabbit anti-human χ antibody and (c) reacted with rabbit anti-human IgGFc antibody. Similarly, (d) shows the FITC profiles of the assembled HMH cells (R) and P3U1 (L) treated with a rabbit anti-human Ig antibody, (e) with a rabbit anti-human χ chain antibody and (f) with rabbit anti-human IgGFc antibody.
Analyse der DNA, die in die HMH-Zellen eingeführt wurdeAnalysis of DNA introduced into HMH cells
Gemäß dem vorstehend beschriebenen Verfahren werden DNA undPoly-A-haltige RNA aus HMH-Zellen isoliert. Wie die ausHMH-Zellen isolierte DNA wird die aus C57BL/6Mausnierenzellen und P3U1 Zellen isolierte DNA mit BamHI abgebaut undeiner Southern Hybridisierung mittels einer Maus-Jχ-Sonde,einer menschlichen Cχ-Sonde, einer Maus-JH-Sonde, und einermenschlichen Cγ-Sonde unterworfen. Das Ergebnis ist in denFig. 4(a), (b), (c) und (d) gezeigt.According to the method described above, DNA and poly-A-containing RNA are isolated from HMH cells. Like the DNA isolated from HMH cells, the DNA isolated from C57BL/6 mouse kidney cells and P3U1 cells is digested with BamHI and subjected to Southern hybridization using a mouse Jχ probe, a human Cχ probe, a mouse JH probe, and a human Cγ probe. The result is shown in Fig. 4(a), (b), (c) and (d).
Hinsichtlich der menschlichen Cχ und Maus-Jχ-Sonden wirdeine 5,9 Kb-Bande, die der Größe eines BamHI-insertiertenpSV2-HC VD10 entspricht, in aus HMH-Zellen isolierte DNAdetektiert. Hinsichtlich der Maus JH-Sonde wird eine 5,5Kb-Bande, die der Größe eines EcoRI-insertierten-Fragments,das das VH-Gen enthält, entspricht, in der DNA aus den HMH-Zellen detektiert. Hinsichtlich der menschlichen Cγ1-Sondewird ein EcoRI-BamHI-insertiertes- pSV2-HGIVD10-Fragment,das das Cγ1-Gen enthält, in der DNA aus den HMH-Zellendetektiert.Regarding the human Cχ and mouse Jχ probes, a 5.9 Kb band corresponding to the size of a BamHI-inserted pSV2-HC VD10 is detected in DNA isolated from HMH cells. Regarding the mouse JH probe, a 5.5 Kb band corresponding to the size of an EcoRI-inserted fragment containing the VH gene is detected in DNA from HMH cells. Regarding the human Cγ1 probe, an EcoRI-BamHI-inserted pSV2-HGIVD10 fragment containing the Cγ1 gene is detected in DNA from HMH cells.
Gemäß diesen Tatsachen ist offensichtlich, daß dieHMH-Zellen die intakten chimeren Gene sowohl für die schwere alsauch die leichte Kette im Genom besitzen.According to these facts, it is obvious that the HMH cells possess the intact chimeric genes for both the heavy and light chains in the genome.
Poly-A-haltige mRNAs, die aus HMH-Zellen und P3U1 isoliertwurden, werden zur Durchführung eines Northern Blots miteiner VJχ14-Sonde, einer menschlichen Cχ-Sonde, einerVJH243-Sonde bzw. einer menschlichen Cγ1Sonde verwendet.Mit Hilfe der VJχ14-Sonde und der menschlichen Cχ-Sondewird eine 1,2 Kb-Bande, die vermutlich die gleiche Größewie die χ-Ketten-erzeugenden Zellen besitzt, als mRNA derL-Kette in dem chimeren Antikörper detektiert.Poly-A-containing mRNAs isolated from HMH cells and P3U1 are used to perform Northern blot with a VJχ14 probe, a human Cχ probe, a VJH243 probe, and a human Cγ1 probe, respectively. Using the VJχ14 probe and the human Cχ probe, a 1.2 Kb band, presumably the same size as the χ chain-producing cells, is detected as L-chain mRNA in the chimeric antibody.
Eine 5 Kb-Bande wird als mRNA-Primärtranskript detektiert,dessen Intron nicht entfernt ist, weil das Splicing nochnicht eingetreten war (siehe Fig. 4B(a) und (b)). ZweiBanden werden bei 3,5 und 7 Kb mit Hilfe von VJH 243 undC&sub1;-Sonden hinsichtlich der mRNA der HMH-Zellen detektiert.Ausgedrückt als Dimension entspricht das zuerst genannteder mRNA der Membran-ständigen γ-Kette vom Typ H und diezuletzt genannte der mRNA, deren Intron noch nicht entferntwurde, weil es ein Primärtranskript war.A 5 Kb band is detected as a primary mRNA transcript whose intron is not removed because splicing has not yet occurred (see Fig. 4B(a) and (b)). Two bands are detected at 3.5 and 7 Kb using VJH 243 and C1 probes for the HMH cell mRNA. Expressed as a dimension, the former corresponds to the H-type membrane γ-chain mRNA and the latter to the mRNA whose intron has not yet been removed because it was a primary transcript.
Wie aus den obigen Ergebnissen sehr gut hervorgeht, istoffensichtlich, daß in den Teilen der primärtranskriptiertenRNA ein Splicing zwischen von der Maus abgeleiteten V-(D)-J-Exons und von den vom Menschen abgeleiteten Exons in HMH-Zellen eintritt.As clearly shown by the above results, it is obvious that in the parts of the primary transcribed RNA, splicing between mouse-derived V-(D)- J exons and human-derived exons enter HMH cells.
Obwohl diese Erfindung in ihrer bevorzugten Ausführungsformmit einem gewissen Ausführlichkeitsgrad beschrieben wurde,ist zu verstehen, daß die vorliegende Beschreibung derbevorzugten Ausführungsform in den Konstruktionsfeinheitenund der Kombination und der Anordnung der Teile verändertwerden kann, ohne vom Sinn und Umfang der nachstehendbeanspruchten Erfindung abzuweichen.Although this invention has been described in its preferred embodimentwith a certain degree of particularity,it is to be understood that the present description of thepreferred embodiment may be changed in the details of constructionand the combination and arrangement of partswithout departing from the spirit and scope of the invention as hereinafter claimed.
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP16937084AJPS6147500A (en) | 1984-08-15 | 1984-08-15 | Chimeric monoclonal antibody and its production method |
| Publication Number | Publication Date |
|---|---|
| DE3587360D1 DE3587360D1 (en) | 1993-07-01 |
| DE3587360T2true DE3587360T2 (en) | 1993-10-14 |
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE19853587360RevokedDE3587360T2 (en) | 1984-08-15 | 1985-03-08 | Process for the production of chimeric monoclonal antibodies. |
| DE1985102665PendingDE171496T1 (en) | 1984-08-15 | 1985-03-08 | CHIMERIC MONOCLONAL ANTIBODY AND METHOD FOR THE PRODUCTION THEREOF. |
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE1985102665PendingDE171496T1 (en) | 1984-08-15 | 1985-03-08 | CHIMERIC MONOCLONAL ANTIBODY AND METHOD FOR THE PRODUCTION THEREOF. |
| Country | Link |
|---|---|
| EP (1) | EP0171496B1 (en) |
| JP (1) | JPS6147500A (en) |
| CA (1) | CA1339201C (en) |
| DE (2) | DE3587360T2 (en) |
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| DE3587360D1 (en) | 1993-07-01 |
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